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81.
Alexsander K. Bressan Michael Wahba Elijah Dixon Chad G. Ball 《HPB : the official journal of the International Hepato Pancreato Biliary Association》2018,20(1):20-27
Background
Pancreatic fistula remains a major complication after pancreaticoduodenectomy (PD). Re-operation is generally considered only after exhaustion of non-surgical options. A variety of pancreas-preserving operations have been proposed, but completion pancreatectomy (CP) stands out in locally complicated cases as a universal approach. This study aims to provide a qualitative synthesis of the peer-reviewed literature regarding emergency CP for post-PD pancreatic fistula.Methods
A systematic search of PubMed and EMBASE for all studies reporting clinical outcomes for CP in the acute treatment of pancreatic fistula following PD from January 1975 until May 2016.Results
Eleven patient-series with a total of 5566 PD and 151 (3%) emergency CP were included. Median time from PD to CP ranged from 6 to 17 days (7 studies), and mean operative time and blood loss – reported in only two studies – were 197 min and 2173 mL respectively. Re-laparotomy following CP was required in 35% of patients. Median hospital length-of-stay varied from 21 to 64 days, and postoperative mortality was 42%.Conclusions
Emergency surgery for postoperative pancreatic fistula should only be considered after expert consultation. CP carries a high risk of mortality, and it is most commonly recommended for a selected subgroup of patients with locally complicated fistula. 相似文献82.
Acute Myeloid Leukemia (AML) is a disorder affecting primarily elderly individuals and poses significant treatment challenges. Much has been learned about the underlying immunologic, cytogenetic and molecular features of AML in recent years, and many features have been identified that portend a poor prognosis for elderly patients with newly diagnosed AML. Despite this, treatment outcomes for elderly patients remain poor for both newly diagnosed and relapsed disease. While conventional treatment approaches may be appropriate for some elderly patients, the vast majority do not tolerate intensive chemotherapy well, thus alternative strategies have been investigated. Here we review both conventional and novel treatment approaches for elderly patients with AML, including agents in early clinical trials. Treatment options have been divided into several discussions, including conventional treatments, agents complementary to conventional treatments, alternatives to conventional induction therapies, post-induction treatment, and relapsed disease. Current and developing research focuses upon identifying subgroups of patients that benefit more from specific chemotherapeutic agents. Treating elderly patients with AML requires an organized, multidisciplinary approach, taking into account individual patient characteristics, preferences, and comorbidities when formulating treatment plans. 相似文献
83.
J. Devon Roll Ashley G. Rivenbark Rupninder Sandhu Joel S. Parker Wendell D. Jones Lisa A. Carey Chad A. Livasy William B. Coleman 《Experimental and molecular pathology》2013
A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes — basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan–Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers. 相似文献
84.
Eric D. Holbrook Katherine A. Smolnycki Brian H. Youseff Chad A. Rappleye 《Infection and immunity》2013,81(7):2334-2346
Histoplasma capsulatum is a respiratory pathogen that infects phagocytic cells. The mechanisms allowing Histoplasma to overcome toxic reactive oxygen molecules produced by the innate immune system are an integral part of Histoplasma''s ability to survive during infection. To probe the contribution of Histoplasma catalases in oxidative stress defense, we created and analyzed the virulence defects of mutants lacking CatB and CatP, which are responsible for extracellular and intracellular catalase activities, respectively. Both CatB and CatP protected Histoplasma from peroxide challenge in vitro and from antimicrobial reactive oxygen produced by human neutrophils and activated macrophages. Optimal protection required both catalases, as the survival of a double mutant lacking both CatB and CatP was lower than that of single-catalase-deficient cells. Although CatB contributed to reactive oxygen species defenses in vitro, CatB was dispensable for lung infection and extrapulmonary dissemination in vivo. Loss of CatB from a strain also lacking superoxide dismutase (Sod3) did not further reduce the survival of Histoplasma yeasts. Nevertheless, some catalase function was required for pathogenesis since simultaneous loss of both CatB and CatP attenuated Histoplasma virulence in vivo. These results demonstrate that Histoplasma''s dual catalases comprise a system that enables Histoplasma to efficiently overcome the reactive oxygen produced by the innate immune system. 相似文献
85.
Bharat Bhushan Prachi Borude Genea Edwards Chad Walesky Joshua Cleveland Feng Li Xiaochao Ma Udayan Apte 《The American journal of pathology》2013,183(5):1518-1526
Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)–induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)–containing diet for bile acid depletion, or a 0.2% cholic acid (CA)–containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet–fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury.Bile acids are versatile biological molecules that regulate energy homeostasis, activate nuclear receptors and cell signaling pathways, and control cell proliferation and inflammatory processes in the liver and gastrointestinal tract.1,2 Bile acids maintain their own homeostasis by activating a complex signaling network involving hepatic and intestinal farnesoid X receptor (FXR), small heterodimer partner, and intestinal fibroblast growth factor (FGF) 15 (FGF19 in human) expression, culminating in inhibition of the primary bile acid–synthesizing enzyme, CYP7A1.3–6 Although bile acids are potent signaling molecules at pathophysiological concentrations, they cause apoptosis, necrosis, and oxidative stress.3,7–10 Bile acids have also been implicated in stimulation of liver regeneration.11–14 Studies in recent years indicate that the bile acid–mediated gut-liver signaling axis may play a critical role in regulation of liver homeostasis.6,15,16Acetaminophen (APAP) is the most commonly used analgesic and antipyretic agent.17 An overdose of APAP is the major cause of acute liver failure in the United States.18,19 The mechanisms of APAP-induced liver injury and subsequent liver regeneration are the focus of intense investigation.20–22 In an overdose situation, excess APAP is mainly metabolized by CYP2E1 to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). In hepatocytes, conjugation of NAPQI to GSH is the key mechanism for detoxification of NAPQI. Once the GSH is depleted, NAPQI attacks cellular proteins, especially mitochondrial proteins, to form protein adducts. This triggers a cascade of intracellular signaling events involving c-Jun N-terminal protein kinase (JNK) activation and mitochondrial permeability transition, finally culminating in necrotic cell death.20 Liver injury is followed by compensatory liver regeneration, which is a critical determinant of final outcome of liver injury.23 Despite decades of research, how these intracellular events are affected by extracellular signaling is not known.The current study was designed to explore the role of bile acids in initiation of liver injury and stimulation of liver regeneration after APAP overdose. These studies are highly significant because the data reveal a novel role of bile acids in cellular protection and liver regeneration after APAP overdose, and these studies investigate the effect of resin-mediated bile acid depletion, a commonly used therapy, on APAP toxicity. 相似文献
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